More than 40 million people are infected worldwide with HIV-1 and an estimated 14,000 new infections occur every day. Over 25 million people have died of HIV/AIDS since the first cases of AIDS were identified in 1981 (CDC, MMWR Morb. Mortal Wkly. Rep., 52:1145-1148, 2003; UNAIDS, 2003 Report on the Global AIDS Epidemic Executive Summary, 2004). Development of a globally relevant HIV-1 vaccine is critical for controlling the HIV/AIDS pandemic.
The combination of a high transcriptional error rate and frequent recombination results in a remarkable amount of genetic diversity among HIV-1 strains and presents a challenge for selecting viral antigens. The other potential impact of HIV genetic variation is the high rate of mutation within each individual, which creates the opportunity for viral escape from epitope-specific immune responses and poses particular challenges for T cell based vaccine approaches (Altfield et al., J. Virol., 77:12764-12772, 2002; Bhardwaj et al., Nat. Med., 9:13-14, 2003; Brander et al., Curr. Opin. Immunol., 11:451-459, 1999; Letvin et al., Nat. Med., 9:861-866, 2003). A variety of vaccine strategies to elicit effective immunity to HIV-1 have been explored. Among them, immunization by plasmid DNA encoding genes for HIV protein antigens is a promising vaccine approach (Mascola et al., Curr. Opin. Immunol., 13:489-494, 2001; Nabel, G. J., Nature, 410:1002-1007, 2001). Gene-based immunization promotes host cell synthesis and expression of the viral antigen and physiologic post-translational processing and folding in the cell cytoplasm. Therefore, DNA immunization elicits both CD4+ and CD8+ T lymphocyte responses with a variety of immunogens in animal models (Graham, B. S., Annu. Rev. Med., 53:207-221, 2002; Rollman et al., Gene Ther., 11:1146-1154, 2004; Barouch et al., Science, 290:486-492, 2000; Subbramanian et al., J. Virol., 77:10113-10118, 2003; Mascola et al., J. Virol., 79:771-779, 2005).
Delivering viral antigens by DNA plasmid vaccine vectors has potential advantages over other vector delivery systems, notably the lack of anti-vector immunity. However, DNA immunization has shown only limited immunogenicity in humans, despite many examples of vaccine-induced protection in mice and nonhuman primates (Rollman et al., Gene Ther., 11:1146-1154, 2004; Donnelly et al., Nat. Med., 1:583-587, 1995). The first DNA vaccine demonstrated to be immunogenic in antigen-naïve humans was a construct expressing the circumsporozoite antigen from Plasmodium falciparum delivered by Biojector®. In this study, CD8+ CTL responses were detected only after in vitro expansion of effectors (Wang et al., Science, 282:476-480, 1998). Another report described a DNA plasmid expressing the Hepatitis B surface antigen delivered by a different needleless injection device, Powderject™, induced antibody as well as vaccine-specific T cell responses in antigen-naïve humans (Roy et al., Vaccine, 19:764-778, 2000). A DNA plasmid vaccine expressing the HIV-1 Env and Rev proteins tested in both HIV-infected and HIV-uninfected subjects (MacGregor et al., J. Infect. Dis., 178:92-100, 1998) was not associated with adverse events, but only sporadic lymphoproliferative and antibody responses were observed (MacGregor et al., J. Infect. Dis., 181:406, 2000; MacGregor et al., AIDS, 16:2137-2143, 2002).
This disclosure describes vaccine compositions that elicit broad spectrum immunity against HIV, by providing robust expression of HIV antigens corresponding to important immunogenic epitopes of multiple clades and strains of human immunodeficiency virus 1. The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.